Transcriptional Regulation of Adipogenesis by KLF4

Laboratory of Molecular Genetics, Rockefeller University, New York, NY 10021, USA.
Cell Metabolism (Impact Factor: 17.57). 05/2008; 7(4):339-47. DOI: 10.1016/j.cmet.2008.02.001
Source: PubMed


While adipogenesis is known to be controlled by a complex network of transcription factors, less is known about the transcriptional cascade that initiates this process. We report here the characterization of Krüppel-like factor 4 (KLF4) as an essential early regulator of adipogenesis. Klf4 is expressed in 3T3-L1 cells within 30 min after exposure to a standard adipogenic cocktail of insulin, glucocorticoids, and IBMX. Knockdown of KLF4 inhibits adipogenesis and downregulates C/EBPbeta levels. KLF4 binds directly to the C/EBPbeta (Cebpb) promoter as shown by chromatin immunoprecipitation and gel shift assays and, together with Krox20, cooperatively transactivates a C/EBPbeta reporter. C/EBPbeta knockdown increases levels of KLF4 and Krox20, suggesting that C/EBPbeta normally suppresses Krox20 and KLF4 expression via a tightly controlled negative feedback loop. KLF4 is specifically induced in response to cAMP, which by itself can partially activate adipogenesis. These data suggest that KLF4 functions as an immediate early regulator of adipogenesis to induce C/EBPbeta.

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Available from: Zhu Chen, Mar 08, 2014
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    • "The designated cells undergo a terminal differentiation that is apparent by both the production of lipid droplets and the emergence of many metabolic factors unique to a developed fat cell. During the entire differentiation process there are several essential molecular interactions that occur among members of C/EBP, the PPAR and ADD1/SREBP1c [132]. C/EBPβ and C/ EBPδ induce PPARγ, which in turn initiates the adipogenic program that is required to promote fat cell differentiation [8] [133]. "
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    ABSTRACT: Background: Lipid metabolism dysfunction leading to excess fat deposits (obesity) may cause tumor (cancer) development. Both obesity and cancer are the epicenter of important medical issues. Lipid metabolism and cell death/proliferation are controlled by biochemical and molecular pathways involving many proteins, and organelles; alteration in these pathways leads to fat accumulation or tumor growth. Mammalian Krüppel-like factors, KLFs play key roles in both lipid metabolism and tumor development. Scope of review: Substantial epidemiological and clinical studies have established strong association of obesity with a number of human cancers. However, we need more experimental verification to determine the exact role of this metabolic alteration in the context of tumor development. A clear understanding of molecules, pathways and the mechanisms involved in lipid metabolism and cell death/proliferation will have important implications in pathogenesis, and prevention of these diseases. Major conclusion: The regulatory role of KLFs, in both cell death/proliferation and lipid metabolism suggests a common regulation of both processes. This provides an excellent model for delivering a precise understanding of the mechanisms linking altered expression of KLFs to obesity and tumor development. General significance: Currently, mouse and rats are the models of choice for investigating disease mechanisms and pharmacological therapies but a genetic model is needed for a thorough examination of KLF function in vivo during the development of an organism. The worm Caenorhabditis elegans is an ideal model to study the connectivity between lipid metabolism and cell death/proliferation.
    Biochimica et Biophysica Acta (BBA) - General Subjects 11/2014; 1850(2). DOI:10.1016/j.bbagen.2014.11.004 · 4.38 Impact Factor
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    • "Most of these are highly enriched (>10-fold) in the C/EBPb immunoprecipitation compared with the nonspecific immunoglobulin G (IgG) control, indicating a strong and specific association with C/EBPb. Several of the transcription factors identified as C/EBPb-interacting proteins by proteomics analysis have also been shown to regulate the early phase of adipocyte differentiation , e.g., KLF4 (Birsoy et al., 2008), KLF5 (Oishi et al., 2011), GR (Siersbaek et al., 2011; Steger et al., 2010), and PBX1 (Monteiro et al., 2011), clearly indicating that our approach is a powerful strategy for identifying biologically meaningful regulators of the differentiation process. A comparison of the identified proteins with our previously published de novo motif analysis of DNA sequences at DHS regions identified at the 4 hr time point (Siersbaek et al., 2011; Figure S1A, right) revealed binding motifs for many of the transcription factors identified as C/EBPb-associated proteins (Figure 2C). "
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    ABSTRACT: It is becoming increasingly clear that transcription factors operate in complex networks through thousands of genomic binding sites, many of which bind several transcription factors. However, the extent and mechanisms of crosstalk between tran-scription factors at these hotspots remain unclear. Using a combination of advanced proteomics and genomics approaches, we identify 12,000 tran-scription factor hotspots (400 bp) in the early phase of adipogenesis, and we find evidence of both simul-taneous and sequential binding of transcription fac-tors at these regions. We demonstrate that hotspots are highly enriched in large super-enhancer regions (several kilobases), which drive the early adipogenic reprogramming of gene expression. Our results indi-cate that cooperativity between transcription factors at the level of hotspots as well as super-enhancers is very important for enhancer activity and transcrip-tional reprogramming. Thus, hotspots and super-enhancers constitute important regulatory hubs that serve to integrate external stimuli on chromatin.
    Cell Reports 06/2014; 7(5):1443-1455. DOI:10.1016/j.celrep.2014.04.042 · 8.36 Impact Factor
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    • "Several members of KLF family of zinc-finger TFs, including KLF4, KLF5, KLF9 and KLF15, are induced at various stages of 3 T3-L1 adipogenesis. KLF4 and KLF5 mRNA levels are induced in the early phase of adipogenesis and peak at around 2 h and 6 h, respectively [58,59]. KLF9 and KLF15 mRNA levels are induced at day 2–4 of 3T3-L1 adipogenesis and peak at around day 6–8 [60,61]. "
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    ABSTRACT: The nuclear receptor PPARγ is a master regulator of adipogenesis. PPARγ is highly expressed in adipose tissues and its expression is markedly induced during adipogenesis. In this review, we describe the current knowledge, as well as future directions, on transcriptional and epigenetic regulation of PPARγ expression during adipogenesis. Investigating the molecular mechanisms that control PPARγ expression during adipogenesis is critical for understanding the development of white and brown adipose tissues, as well as pathological conditions such as obesity and diabetes. The robust induction of PPARγ expression during adipogenesis also serves as an excellent model system for studying transcriptional and epigenetic regulation of cell-type-specific gene expression.
    Cell and Bioscience 05/2014; 4(1):29. DOI:10.1186/2045-3701-4-29 · 3.63 Impact Factor
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